Production of 17-hydroxy 20-keto steroid compounds



Patented July 24, 1951 23';

PaonUoTIonioE l'l HYDROXY zc-xa'rd' V y .s'r Roip COMPOUNDS? Thomas Gallagher, nus'hjiiigflulv aiidrheo dore H.":Kritche'vsky, Chi'Qfl mIll] Research Corporation, Xork,

poration of New York;

' Noni-a This invention relates to a methodfor the introduction of a tertiary alcohol group at'Cl'le'of the steroid nucleus of steroid compoundscontaininga carbon side chain at C17. The method of the invention is particularly useful as a step in the preparation of substances having the prop- ,erties'of the 1'7-hyclroxy' adrenal cortical-hormones, such as-17 hydroxy-desoxycorticosterone (Reichsteins Compound S) and l'l-hydroxy-lldehydrocorticosterone (Kendalls Compound E) Example I 1.51 g. of amorphous preparation of 3a,20-diacetoxy-A -pregnene, as prepared by the procedure of Marshall et al. (J. Am. Chem. Soc., 70, 1837, 1948) is dissolved in 8 ml. of a chloroform solution containing 0.69 g. of perbenzoic ample I can be converted into 17-hydroxy-desoxycorticosterone (Reichsteins Compound S) by the following series of reactions:

The formate of 3a,l'h-dihydroxypregnan-ZO- one is brominated with approximately 1 mole of bromine in glacial acetic acid solution. 5.93 g. of 3a-formoxy-17a-hydroxypregnan-20-one are suspended in 60 cc. of glacial acetic acid and 32.8 cc. of 0.5 molar bromine in acetic acid are added. cc. of a solution of HBr in glacial 'g'. "spamming/e1, 1950. crial .10.6261. 9 Claims. (01. zet semlj" g acetic'acid are added to the mixture and in the vcourse of 30.,minutes the solution decoloriz je's. IfIfhe cprresponding '21-bromoproduct is obtained by"ether"extraction." g. Q

- 3.75. g. of v the .3,a form0xy -17a hydroxy- 2lbroe mopregnan zfl'one are dissolved in 0 cc. redisstilled'methanol and 80 cc. of 1.2,N'dry hydra en chlorid'e'in methanol are; added tojthe cold sol -Q tion. Thesolution is stored overnight at 5C. and the solvent is [removed underv diminished pressure'at'a low temperature. The, neutral prod:

uct is" removed by ethepez traction' and isolated after washing with waterjdilute, sodium carbonate solution and water and ,removal, of, the solvent. After recrystallization from ethyl; acetate the product melts at"202-'-204 C..., 3;3 ggbf this product, namely, .3u,17a-dihydr'0xy1- 2l bi'omOpregnanAZO-one are dissolved in cc, tertiary butanol, and 2.1 g. of Nebromoacetani idafl cc. of pyridine andLScc, water are added. The solution is stored at 5 Cffor l6 hoursandtheprod;

uct is isolated by ether extraction followed by washing with dilute acid, water and dilute carbonate solution and again with water. The sol vent is removed and the crystalline residue 17a.-

hydroxy-2l-bromopregnane-3,20-dione melts at 203-204 C.; [a] =+81 (ethanol). It is saponifled to the corresponding 21-hydroxy compound as follows: 201 mg. of the zl' -bromo compound are dissolved in 100 ml. 01' per cent ethanol. 88 cc. of water are added and the solution is flushed. well with nitrogen gas. 12 cc. of approximately normal NaOH are added. After ten minutes most of the halogen is ionic. The solution is then extracted with ether and washed with dilute alkali and with dilute brine. The neutral fraction crystallizes upon removal of the solvent. The neutral product of hydrolysis is acetylated with pyridine and acetic anhydride and separated from a small amount of impurity by chromatography. The product, which is l'la-hydroxy-zl-acetoxypregnane-3,20-dione, melts at 199 0.;

It is converted to the acetate of Reichsteins Compound S by bromination in glacial acetic acid with one mole of bromine followed by removal of HBr from the product by means of pyridine, dinitrophenylhydrazine or other dehydrohalogenating agent.

Example II In a similar fashion 3p,17c-dihydroxy-allopregnan-ZO-one is prepared from the enol acetate of allopregnanolone (3,20-diacetoxyA -preg- 485 mg. of the diendiol triacetate of 3111-11 droxypregnan-l1,20-dione in 3 p m1. benzene are treated with 3.5 ml. of 1.75M perbenzoicBpid' 2. A method which comprises subjecting an enol carboxylic acid ester of a 20-ketosteroid to the action of an organic peracid in an organic liquid solvent and saponifying the product to produce the corresponding 17-hydroxy-20-ketosteroid;

3. A method which comprises subjecting an enol carboxylic acid ester of a ZO-ketosteroid to solution in benzene. The solutionjwarms'spon,

taneously. After standing 'two hours at room temperature the product is isolated by ether extraction followed by washing witfidilute-allcali' The reaction product melts at and water. 193-194 C.; [a] =+74.2 C. (chloroform); Upon saponification with excess alkali in 50 per cent ethanol solution. at room temperature for about 30 minutes, the neutral productjfrom the reaction is isolated by ether'extraction It is SaJ'Ie-dihydrQXypre'gnan-ILZOedionejor melting point 198-2 1 0. g j p By' methods analogoustop those, described in Example II for the preparation of Reichs'teins Co po ds the i -d h rbxy c 'nanrl1,20- dione may be convelted into."'l7-lhydiioxy lldehydrocortico'sterone j '(Kendalls Compound E) Other organic peracids may be substituted in equimo'lecular amounts for. the rperbei zjoiq r ncid inthe foregoing exam ies; f V I 'Th" application'fisa ch tinuation-in-part of our application Serial No. 1 1546c filed September 28,1949, now abandoned} la j i J l l qA method which comprises subjecting an enol carboxylic acid' ester o'ifagfl k etosteroid to the action of an organic peracid and saponifying the product to produce the corresponding 17 hydroxy 20-ketosteroid. C f

theaction of perbenzoic acid in an organic liquid solvent and saponifying the product to produce the corresponding l'l-hydroxy-ZO-ketosteroid.

4. A method which comprises subjecting an enol acetate of a ZO-ketosteroid to the action of perbenzoic acid in an organic liquid solvent and sapomrymg the product to produce the corresponding. 1'7 -hydroxy-20-ketosteroid.

' 5, A method which comprises subjecting 311,20- diacetoXy- A -pregnene to the action of perbenzoic acid and saponifying the product to produce 311,17 a-dihydroXy-pregnan-20-one.

6. A methodwhich comprises subjecting the diendiol triacetate of 3a-hydrOXy-pregnan-ILZO dione to the action of perbenzoic 'acid and saponifying the product to produce 3u,17a-dihydroxy-pregnan-ll,20-dione.

'7. In the production of l7-hydroxy-20-ketosteroids the step which comprises subjecting an enol carboxylic acid ester of a 20-ketosteroid to the action of an organic peracid.

8. In the production of 17-hydroxy-desoxycorticosterone, the step which comprises subjecting 3(1,20-diacetoxy-A -pregnene to' the action of perbenzoic acid.

9. In the production of l'l-hydroxyr-ll dehydrocorticosterone, the step which comprises subjecting the diendiol triacetate of 3a-hydroxye pregnan-ILZO-dione to the actionof perbenzoic acidn THOMAS E. GALLAGHER.

THEODORE Hi IRITCHEVSK.

' No references cited. 

1. A METHOD WHICH COMPRISES SUBJECTING AN ENOL CARBOXYLIC ACID ESTER OF A 20-KETOSTEROID TO THE ACTION OF AN ORGANIC PERACID AND SAPONIFYING THE PRODUCT TO PRODUCE THE CORRESPONDING 17HYDROXY-20-KETOSTEROID. 